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<p>The importance of astrocytes for Alzheimer’s disease (AD) pathology is increasingly appreciated, yet the mechanisms whereby this cell type impacts neurodegenerative processes remain elusive. Here we show that, in a genetic mouse model with diminished astrocyte stress response, even low levels of amyloid-β trigger astrocyte reactivity, resulting in brain inflammation and massive amyloid and tau pathologies. This dysfunctional response of astrocytes to amyloid-β acts through activation of δ secretase, a stress-induced protease implicated in both amyloid and tau-related proteolytic processing. Our findings identify a failed astrocyte stress response to amyloid-β as an early inducer of amyloid and tau co-morbidity, a noxious process in AD acting through a non-canonical secretase pathway.</p>

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Astrocytes distress triggers brain pathology through induction of δ secretase in a murine model of Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月31日

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  • Vanessa Schmidt,
  • Ewelina Ziemlinska,
  • Tomasz Obrebski,
  • Jemila P. Gomes,
  • Ewa Zurawska-Plaksej,
  • Jaroslaw Cendrowski,
  • Johan Palmfeldt,
  • Barbara L. Hempstead,
  • Thomas E. Willnow,
  • Anna R. Malik

摘要

The importance of astrocytes for Alzheimer’s disease (AD) pathology is increasingly appreciated, yet the mechanisms whereby this cell type impacts neurodegenerative processes remain elusive. Here we show that, in a genetic mouse model with diminished astrocyte stress response, even low levels of amyloid-β trigger astrocyte reactivity, resulting in brain inflammation and massive amyloid and tau pathologies. This dysfunctional response of astrocytes to amyloid-β acts through activation of δ secretase, a stress-induced protease implicated in both amyloid and tau-related proteolytic processing. Our findings identify a failed astrocyte stress response to amyloid-β as an early inducer of amyloid and tau co-morbidity, a noxious process in AD acting through a non-canonical secretase pathway.